Chris Casey:
Welcome to another episode of Health Science Radio, where we talk with researchers at the University of Colorado Anschutz Medical Campus about the ways they are innovating and advancing healthcare. My name is Chris Casey and I am the director of digital storytelling here at CU Anschutz. In studio, at the historic Fitzsimons building, I'm once again joined by my co-host, Dr. Thomas Flaig, our Vice-Chancellor of Research. How are you on this fine, sweltering summer day?
Thomas Flaig:
Doing very well in the historic Fitzsimons building. It's great to be here, and I'm looking forward to the topic today.
Chris Casey:
As am I. Our guest today is Dr. Eduardo Davila, Professor of Medicine and Director of Immunotherapy Medical Oncology at the CU School of Medicine. We will discuss Dr. Davila team's work in advancing immunotherapy treatments for cancer, including tumor-infiltrating lymphocyte or TIL therapy. So a little bit more about Eduardo. He is a 2002 graduate of the Mayo Clinic Graduate School of Biomedical Sciences. Here at the University of Colorado, Dr. Davila oversees a translational and basic research program that is not focused on any single cancer type and instead on immuno-therapeutic strategies that are applicable across tumor types. So Eduardo, welcome to our program.
Eduardo Davila:
Chris and Tom, thank you so much for the opportunity to hang around with you and discuss a little bit about what my research team and I have been doing over the last few years. This is an exciting opportunity. This is an exciting time for cancer immunotherapy. So thank you again for having me here.
Chris Casey:
Well, we're excited to have you. And perhaps just to get us started off and kind of lay the groundwork of what you do Eduardo, could you just explain a little bit about what inspired you to become a translational scientist?
Eduardo Davila:
Sure. Thank you for the question, Chris. So for audience members that aren't quite familiar with the terminology, a translational scientist really focuses on developing diagnostics or therapies or prognostics that will make it into the patient. Some form of therapy that could be impactful in a relatively short period of time. So my research team and I really are dedicated to serving our community. And this really probably stems from my upbringing as a Mexican-American being led in a matriarchal society by my grandmother who constantly reminded us that we are here on earth to help one another and we are here to serve one another.
So as I think about my career trajectory and what my passions have been ever since college, it really has been to kind of (a matter of) how do I serve my community? And as a scientist, I'm able to do so in different ways. We can train the next generation of scientists through teaching graduate students, we can mentor the next generation of physician-scientists or physicians through types of different mentorship programs. So really I think this is just a real blessing to be able to love what I do and do what I love. So as a translational scientist, I can really reach out to different members of the community, including patients.
Chris Casey:
And you were, as part of the panel that chatted just last week with President Joe Biden's chief advisor on science here on campus. I was just curious what your thoughts were on her visit. That's Dr. Arati Prabhakar, I believe I'm pronouncing that reasonably close.
Eduardo Davila:
Yeah.
Chris Casey:
She's overseeing the Cancer Moonshot program and so that's very timely and it seems to be a program that's gaining steam. Could you just talk about what you shared with her as to what we're doing here that's relevant?
Eduardo Davila:
Yeah, so first let me share what an honor it was for our campus and our leadership to have been visited by Dr. Prabhakar. It really highlights the important work that our university, our campus, our oncologists are doing. That we were recognized with her presence and her visit really speaks to the strength of our program here. So regarding your question, so what I shared with her was what I've shared with you is really the intensity of the passion for, and our mission for serving our community.
And our community is not necessarily just our graduate students, our medical students, it really extends beyond that. Our community consists of clinical fellows, residents, junior faculty, as well as beyond just our academic community. We in the cancer center, one of our missions is how do we cure cancer together. And that together really encompasses everybody, including community members outside our academic campus.
And so a lot of our focus extends beyond this. What happens when we move three blocks out into the neighborhoods? Do those communities understand what we do? Do those communities really know that we are here to serve them when their loved ones or they are afflicted unfortunately with cancer? So we shared this with her and her response was I think very heartfelt and I think she appreciates the importance of having the navigators in place, dedicated oncologists, nurses, nurse practitioners, the whole community that makes patient care the top-notch service that it is on our campus.
Thomas Flaig:
Yeah, I appreciate your comments. We're here in the historic Fitzsimons building. It opened up just about the start of the Americans’ involvement in World War II. But our physical plant's pretty new here. Our campus has grown really quickly in the last few years. And so I think it's great to have such prominent people come to campus and see what we have here. But it's also important to your point, to think about our community, right? We are relatively new to this part of the metro Denver area. It's really important to foster and facilitate those connections locally, nationally, and internationally. So again, in so many ways, it's great to have her on campus.
Eduardo Davila:
Yeah, great point.
Chris Casey:
And shifting gears a bit to a little bit more detail about the research your team is doing, Eduardo, could you just talk a little bit about this project you're working on with your team through the Anschutz Acceleration Initiative and what's the goal? It's on a pretty accelerated timeline, as I understand, to try to have some real material benefit to patients within a pretty limited amount of time.
Eduardo Davila:
Yeah, Christopher, thank you so much for that question. So first, let me express my and my team's appreciation and gratitude to the Anschutz family, the Gates family.
This is the type of opportunity that is incredibly rare in academia, but it is also the type of opportunity that can accelerate a new therapy to a patient. So the cancer therapy we are developing leverages the patient's immune system to naturally recognize cancer. And I'm going to back up a little bit. So what the audience may or may not know is that our immune system has been tasked with quite a bit to keep us alive and to keep us protected against a variety of viral infections, fungal infections, to keep a lot of the rest of our systems kind of in place.
And what people often don't realize is that one of the jobs of our immune system is to recognize and destroy cancer. Now, when individuals develop cancer, it is for a variety of reasons. One of those reasons is because our immune system has either been overwhelmed or simply incapable of doing its job in destroying cancer. One form of therapy, which you refer to as TIL therapy, tumor-infiltrating lymphocyte therapy, which I'll refer to as TIL therapy, is an interesting form of therapy that has actually been around for about 30 years. However, for a variety of reasons, it hasn't really made it into the general public.
It's been clinically tested, it's been confirmed to be safe, but it just doesn't have enough of that power to kind of get the job done in most patients. So TIL therapy consists, basically it's a procedure in which a tumor is surgically resected from a patient then the immune cells that do recognize and can kill the cancer are extracted from that tumor. In conventional form of TIL therapy, these cells are grown to a very large number in the clinical laboratory and infused back into the patient.
Now, in a subset of patients, let's say with advanced melanoma, about 30% that receive this form of therapy, incredible responses, great durable responses that are quite long-lived. Unfortunately, if you think about an immune cell inside a tumor, it's very much like thinking about a boxer inside a ring or an MMA fighter inside a ring where you go round after round after round, fighting, fighting, fighting. The immune cells are outnumbered, sometimes a million to a billion to 1. So it's the immune cells’ job to recognize each individual cancer cell and kill it one at a time.
So just like any trained athlete, they will become tired; they will become exhausted. So these immune cells that are present undergo this stage, this differentiation, this evolution into an exhausted T-cell. In addition to that, that immune cell is kind of aged prematurely because as you fight more and more and more, you do become tired and exhausted and you become aged.
So what my research team and I have been working on over the last decade is to identify methods through which we can rejuvenate them, make them strong again, make them young again, make them better than they were before. So we've accomplished this through a genetic engineering in which we have developed an artificial or synthetic gene, which we incorporate into the immune cell, which makes it live longer, kill better, and just be more effective, find the cancer easier.
So when I was a child, I used to watch this television show called The Million Dollar Man. The Bionic Man.
Chris Casey:
Oh, I watched that. Sure, yeah. Lee Majors.
Eduardo Davila:
Yeah, that's right. Lee Majors. And what I remember in that show is you jump farther and run faster and whatever the case is, and these immune cells are very much those types of cells, that's just much more powerful. So we've incorporated a very unique step into the tail manufacturing process, which we now have evidence for in different models, makes them much better.
Thomas Flaig:
This is really helpful to think through it. Immunotherapy, you think back, we've had chemotherapy for decades, we've had targeted therapy looking at an enzyme or a receptor for less time, but they played an important role. And then I would say as a medical oncologist, I've watched in the last few years the emergence of cellular immunotherapy and I would put TIL therapy into that larger group. Maybe you could say just a few words though, comparing TIL to CAR-T, another concept that our readers might've heard about and how they're different.
Eduardo Davila:
Yeah. Another great differentiating point, I think it's important to highlight a couple of things. So you're absolutely right, there are different forms of immunotherapy. Now, each of these, as the name implies, is intended to reactivate the patient's immune system to do what it's supposed to do, recognize and destroy cancer. Now, immunotherapies can be classified in different buckets. One of them is known as cellular therapy, as you've pointed out. Cellular therapy consists of T-cells, immune cells called cytotoxic T-cells, which are genetically engineered to express a new receptor on their surface. Some of these are CARs, chimeric antigen receptor T-cells.
The others are just TILs, tumor-infiltrating lymphocytes, non-engineered, just standard kind of TILs. Others are known as TCR or T-cell receptor-engineered T-cells. I mention that because that's likely the next form of cell therapy that's about to be approved is TCR-engineered T-cells. I also say that because we have another platform that is based on that, that is a universal anti-cancer form of therapy, which I'm happy to elaborate on later on.
But the main differences between TIL therapy and CAR therapy are the following. So CAR therapy really relies on the genetic modification to express a single receptor on the cell's surface that recognize one antigen. That is one target on a cancer cell. The advantage to something like that is that form of therapy is very specific to any cell that expresses that one beacon, that one target on the cell. In this case, the more successful forms of therapy targeting B-cell leukemias and lymphomas, which express that single antigen.
In many cases, incredibly effective, near I think 30% of patients have benefit from a durable response rate. 70% don't for a variety of reasons. One reason could be that if the cancer cell is smart enough, it will down-regulate or decrease the expression of that antigen in such a way that the CAR T-cell is no longer capable of recognizing it.
The other disadvantage to CAR therapy is that patients often undergo this terrible side effect known as cytokine release syndrome. In this case, the immune cell is doing its job, it's generating a very robust anti-tumor response, a very robust inflammatory response, which unfortunately can be detrimental to the patient and quite dangerous. Luckily, our teams here on campus have managed to develop different ways to treat these patients and care for these patients, but it still represents a pretty serious side effect.
The other difference is that CAR T-cells are derived typically from the peripheral blood of a patient. So you just get intravenous injection or injection draw blood and take out immune cells and then genetically modify them. Immune cells are relatively healthy and they're easy to obtain.
Now contrasting CAR therapy to TIL therapy. So in TIL therapy, as I pointed out previously, a tumor is surgically removed. Then we do have to go through this process of extracting out just the immune cells from that tumor. So in our case, it takes a little bit longer to generate that form of therapy and then we have to go through this process of generating billions of TILs. And then in our case, we genetically modify them and then infuse them back into the patient.
The advantage that TIL therapy offers over CAR therapy is that these immune cells are already programmed naturally to recognize cancer and they recognize numerous targets on a cancer cell. So if a cancer cell becomes really smart and tries to evade it by down-regulating one particular target on its cell surface, the TIL therapy recognizes 10 more other targets. So it's really difficult for the cancer cell to escape immune detection.
Thomas Flaig:
So CAR-T is more that reprogramming where TIL is more that rejuvenation of the cells that are already there.
Eduardo Davila:
Yeah, well said, well said. So we have a high number of targets to pursue. The other advantage is that, unlike CAR therapies, TILs have now been clinically shown to not elicit this cytokine release syndrome. They actually have very minimal side effects. Now, what is toxic in TIL therapy is that the patient has to undergo this process known as preconditioning. In other words, the patient first has to receive chemotherapy to create space, if you will. It has to eliminate temporarily existing immune cells so that when we infuse our immune cells, there are the growth factors for the tails to engraft and then grow out. So you have lots of immune cells to combat the cancer.
The other disadvantage to TIL therapy is that patients oftentimes have to undergo... well, not oftentimes, they undergo an additional form of therapy called IL-2 cytokine therapy. Now this is a growth factor that helps the TILs reach high numbers in the patients so that they can expand and grow. Unfortunately, IL-2 can be toxic to lots of patients. It can induce different types of cardiovascular disorders and can be quite dangerous.
The form of therapy that we have developed that is funded through the Anschutz Acceleration Initiative actually takes IL-2 toxicity into account. So in the clinical trial that we will initiate through this Anschutz Acceleration Initiative on our campus, we are actually using substantially lower doses of IL-2 which can be deemed much safer because of an innate ability of our therapy, our platform, to actually decrease the dependence on IL-2. We feel that we will not only create a much more effective TIL therapy but perhaps a safer tail therapy as well.
Thomas Flaig:
So the goals of that trial would be both to look at the efficacy of this, but also to see if it could be less toxic ways to deliver this therapy in a broad stroke.
Eduardo Davila:
In a broad stroke, that's in essence true. So this is going to be a phase one clinical trial where we're initially looking at just safety and the feasibility is, can working together with our Gates manufacturing facility on our campus lead to the standard operating procedures and protocols necessary to develop this form of therapy. I'm going to jump ahead and say yes, working together with the Institute, the Gates Biomanufacturing Facility, and my team, I'm sure we're going to be able to develop a clinically manufactured product on campus. And I do believe that as secondary readouts, clinical efficacy as well as beyond safety will be incorporated into it. So we're really excited actually at this new opportunity.
Chris Casey:
And Eduardo, are there certain cancers that you're targeting with this therapy like its tumor-infiltrating lymphocyte, so I am gathering those would be solid tumors. Does the therapy work against, say, blood cancers, or is that more the realm of CAR-T therapy?
Eduardo Davila:
Oh, another really great question. So initially there have been a number of different tumor types that have already been tested for TIL therapy nationwide. These include melanoma, head and neck cancer, lung cancer, breast cancer and several others. And that list is growing almost weekly because the more individuals become aware of TIL therapy and the promise that it holds, more and more institutes nationwide and worldwide are adopting this form of therapy and taking it to the clinical level and seeing can this be effective in this form of therapy.
So for our trial, we are leveraging the great successes already observed in head and neck cancer, in lung cancer. We're also targeting a new and kind of underappreciated form of cancer known as sarcoma. The reason that's important is that sarcoma treatments aren't readily available and most types of sarcomas are unfortunately unresponsive. But we have such a great team on campus that we have the ability really and the volume to begin to explore the possibility of what kind of impact we can make in this form of cancer that really has an unmet need. And Chris, I think you had another question. I'm sorry, what was that question?
Chris Casey:
Oh, whether it would apply at all to say blood cancers.
Eduardo Davila:
Oh, yes. So a technique and approach pioneered by a group at Hopkins have taken a little spin on tumor-infiltrating lymphocytes and developed a slightly different form called marrow-infiltrating lymphocytes. So instead of TIL, they called it MIL. And what they're able to do in that system is certain types of leukemia such as acute myeloid leukemia and several others tend to reside and live in the bone marrow. Now within this niche and within this organ, you can extract tumor-specific or leukemia-specific lymphocytes. So a very similar technology. You go into the bone marrow, you extract these tumor-reactive immune cells against blood-borne leukemias, and then similar procedure, expand the cells and then re-infuse them into the patient. So there is an opportunity to leverage what's been learned in the TIL world and apply it to liquid cancers as well.
Thomas Flaig:
It's been interesting because CAR-T has really resided mostly in the liquid tumors, the blood tumors, and there's been efforts to bring them over to solid organs. A lot of the TIL work, just from my observation, and correct me if I'm wrong, have happened, are occurring in cellular tumors in melanoma, head, neck and so forth, and there's sort of a later move into the blood. It may be because of these antigen, these markers that are necessary for the CAR-T, the more general usability of TILs.
Eduardo Davila:
Yes, great point. So even though the world of using MILs or TILs against liquid cancers is lagging behind, I think there's been so much success in the TIL world that I think that merits further exploration in different tumor types.
Thomas Flaig:
I think you did a great job explaining TIL versus CAR-T. It's really helpful. And just to put a fine point on what you've added to that, TILs have been around for decades, right? I think actually Dr. Rosenberg at the NCI is one of the early people working in this many, many years ago. So it's been around, there's been some interest in it, but suddenly now there's this emergence and there's been some clinical activities seen in different settings. Maybe put a fine point on what your addition and your research has added to what we know about TILs.
Eduardo Davila:
Thank you for that question. So first off, let me just comment that Dr. Rosenberg, a hero to many of us, has in many ways been ahead of the curve and has been ahead of his times. So that TIL therapy has been around for 30 years, is not necessarily attributed to it not being successful. It's just that the technology wasn't quite available to make that more of a fruition and bring it more to patients. Because there's been such an explosion in cell therapies and there's been such a strong recognition of how powerful our immune system can be to combat cancer and to actually cure patients of cancer, there's been kind of a resurgence in a lot of the technologies necessary to make this more of a reality.
And that applies to systems from how do we enrich immune cells, how do we genetically engineer immune cells? How do we grow enough immune cells at the manufacturing level to treat a patient? So the technology has caught up with an old form of therapy, which is now making it a little bit more mainstream. So one of the factors really differentiates what we're doing from what others have done is the really relies around the genetic platform that we've developed.
So the platform is an interesting platform which we again developed, patented, and are now kind of moving forward clinically is the ability to confer an immune cell several really important features. One, it rejuvenates them. Rejuvenation means it kind of takes them to an earlier state in their life where they're a lot more powerful, they're a lot more capable, but they can also give rise to more of themselves. So they kind of clone themselves, grow themselves out through an interesting set of mechanisms that we're still exploring. We're able to rejuvenate what's called telomeres activity, telomerase activity.
So telomeres at the end of the day, control how old an immune cell is. At that level, we're able to make it young again. We're also able to confer the immune cell and the ability to recognize really low levels of antigens. One of the ways that cancer cells evade immune detection as it stated previously, is that they reduce the ability to be seen well, whereas most immune cells are kind of blind and they can't see the cancer cell. Our immune cell now has the shades moved off and a lot more eyes. They can recognize more of that cancer cell now they can see it, detect it more easily.
And then when they do, they're able to basically secrete a lot more proteins to kill that cancer. So I thought I'd mentioned the name of the technology because it's kind of a clever name. One of the molecules that we discovered enhances immune activity called myeloid differentiation Factor 88. The short name is just known MyD88. So we've coined our TILs as MyD TILs because they clone the MyD88 but they're also very mighty in their job.
Thomas Flaig:
That's pretty good.
Chris Casey:
I love the way you explain it in very understandable terms, Eduardo. What about just in general, where are we maybe backtracking a bit to that Cancer Moonshot effort in conjunction with the federal government? I've heard that this year in 2024, there'll be 2 million cancer diagnoses made in the United States, which I believe will be a record number, and that there was just a study that came out recently that the rate of the cancer incidence in the United States is expected to climb in the coming years and it's likely to rise in Generation X. Do you have any explanation as to why, despite the advances we seem to be making and there's the Cancer Moonshot going on in all this research, why cancer still seems like such a tough puzzle to solve and that these rates continue to climb?
Eduardo Davila:
So Chris, again, that's a very alarming statistic and unfortunately it is a true statistic. And we can take a little bit of a step back and then try to understand the population of individuals that are becoming more and more susceptible to cancer. And it's really the younger generation. And what the data is showing right now is that lifestyle factors are a major contributing role to the higher incidence of cancer amongst younger individuals.
Now, lifestyles mean different things, right? But in the United States and in several neighboring countries, obesity continues to be a major challenge. And what oftentimes people don't recognize is that obesity leads to so many downstream effects that ultimately favor the development of cancer and then the growth of cancer. So it's not just a matter of obesity affecting diabetes, which it does, and several other factors. It really directly contributes to just the cancer development and our immune system's inability to control cancer when individuals are kind of more obese.
The other is poor diet. Unfortunately, our immune cells require certain types of nutrients, a certain type of oxygen levels, whereas cancer cells kind of thrive in more sedentary lifestyles. I think the other two is obviously related to physical activity, high alcohol or drug use also contribute to both the immune system's inability to recognize and combat cancer, but at the same time favor environments that the cancer cells just love.
The other point, and this is perhaps a bit more controversial, is I am concerned that over the course of the last few decades, the food that we're eating, it has just been so genetically altered in so many ways, whether it's the meats that we're eating, whether it's the fish that are grown in laboratories or whether it's the vegetables that are grown, what we're eating today is very different from what our ancestors were eating even a hundred years ago, even 50 years ago. Very different.
The way those foods are processed, the way those foods are actually stored in plastic containers, there's so much literature out there supporting the fact that these microplastics are now ubiquitous. They're everywhere in our systems, whether it's in circulation, whether it's in our tears, whether it's in our blood, it's just everywhere.
So it's the foods that we're eating, the drinks that we're drinking, whether it's bottled water, again exposed to microplastics, or whether it's water in the environment, is also being negatively impacted by a variety of pollutants. The air that we're breathing is no longer the same clean air that we were breathing a 100, 200, 300 years ago. Collectively, those factors plus the fact you add that into our lifestyles, you add that into just the genetics of individuals being just more likely to develop certain mutations because of sun exposure, because of carcinogens, whatever the case is, we are unfortunately a victim... so humanity is just a victim of its own progress. And so without getting on a soap box, that's my view of why cancer continues to rise.
Thomas Flaig:
If you think about these somewhat alarming statistics about the potential rise of cancer in younger people, younger adults, and the complexity around that, the idea that the solution may be improved diet, weight management, and exercise are reassuring parts to it. And I think you've highlighted the difficulty though in trying to achieve a relatively simple and straightforward goal of eating better and getting some reasonable exercise.
Eduardo Davila:
I think what we used to say, or what my previous mentor reminds me of, is our goal as translational scientists or as medical oncologists is to be unemployed, is to be jobless.
Thomas Flaig:
I'll do it. I tell patients I'd be so happy if I could do something else.
Eduardo Davila:
So that's really our goal. Is it a goal that we can achieve in our lifetime? Probably not. But it is a goal that if we take on a case-by-case basis, yes. I think the cure to cancer in many patients is here, is now, is today.
Thomas Flaig:
I’ll add one point to that too. I make the same joke to patients, although I mean it. If I could do something else because this wasn't a problem, that'd be great. Chemotherapy is not the thing that's going to change the game. Certain patients have benefits, patients need chemotherapy, sometimes it gives them great benefit, but it's not going to give us that ultimate goal of really changing the game. Immunotherapy, on the other hand, has almost a limitless potential for what we can do. And I think one of the surprising things that patients will say to me, they'll say, we're going to do this to get your immune system going. And they have a sense of that's to fight infections and colds, but not this intrinsic role it has in cancer prevention and management. So I think that's something that's becoming more generally aware over time.
Eduardo Davila:
I completely agree with that, Tom. And if I can just add to it, I think the future of immunotherapy or any therapy for cancer is going to be multifactorial. I think in some patients, they've been blessed that immunotherapy was their magic bullet, and it's a subset of patients, it's a small number of patients, a small percentage. I think the future really relies on understanding how the immune system works and understanding what can we combine with immunotherapy in certain patients for certain cancers.
So combination immunotherapy, whether it's immuno-chemotherapy, immuno-radiotherapy, immune-something-other therapy, I think for different cancer types is going to be the way to go. But we have a really long way to go to understand what is the best combination. When we encounter a patient that has this type of cancer, this type of genetics, how do we select which type of immunotherapy of the numerous types of immunotherapies and combine it with which kind of chemotherapy to make this a synergistic response so that we can say, yeah, we believe based on these statistics, you're going to be cancer-free in a few years. And I think that's kind of where a lot of the newer types of bioinformatics and AI come into play, which again, we are blessed with here at CU AMC such an incredible team of informatics and artificial intelligence that we can make it happen.
Chris Casey:
Well, it's very inspiring to hear about your work, Eduardo, and your team's work, and yeah, it's heartening to hear that perhaps maybe we can, with continued research in the vein of what you folks are doing can unlock these combinations that will eventually, hopefully be the solution for this horrible, horrible disease. And, well, it's been a real pleasure to have you with us, thank you for sharing your time and your expertise with us.
Eduardo Davila:
Chris and Tom, thank you so much for the opportunity to hang around with you guys and share our views.
Thomas Flaig:
Great discussion today. Thanks so much.
